A peptide sequence confers retention and rapid degradation in the endoplasmic reticulum.
A nonlysosomal pathway exists for the degradation of newly synthesized proteins retained within the endoplasmic reticulum (ER). This pathway is extremely selective: whereas some proteins are rapidly degraded, others survive for long periods in the ER. The question of whether this selectivity is due to the presence within the sensitive proteins of definable peptide sequences that are sufficient to target them for degradation has been addressed. Deletion of a carboxyl-terminal sequence, comprising the transmembrane domain and short cytoplasmic tail of the alpha chain of the T cell antigen receptor (TCR-alpha), prevented the rapid degradation of this polypeptide. Fusion of this carboxyl-terminal sequence to the extracellular domain of the Tac antigen, a protein that is normally transported to the cell surface where it survives long-term, resulted in the retention and rapid degradation of the chimeric protein in the ER. Additional mutagenesis revealed that the transmembrane domain of TCR-alpha alone was sufficient to cause degradation within the ER. This degradation was not a direct consequence of retention in the ER, as blocking transport of newly synthesized proteins out of the ER with brefeldin A did not lead to degradation of the normal Tac antigen. It is proposed that a 23-amino acid sequence, comprising the transmembrane domain of TCR-alpha, contains information that determines targeting for degradation within the ER system.
Bonifacino
J S
JS
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892.
Suzuki
C K
CK
Klausner
R D
RD
D000595:Amino Acid Sequence; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism
D010446:Peptide Fragments; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2